Atherosclerosis is a disease characterized by chronically high inflammatory state. Arterial inflammation and endothelial dysfunction play key roles at all stages of the atherothrombotic process. Inflammatory mediators are intimately implicated with the cascade of events leading to atherosclerotic plaque initiation, progression and rupture. Vascular endothelial cells express a variety of adhesion molecules that recruit monocytes when chronically exposed to noxious stimuli or pathological conditions. Adverse conditions such as hyperlipidemia are associated with enrichment of a pro-inflammatory subset of monocytes. These monocytes apparently enter the intima under the influence of chemotactic stimuli and engulf modified low density lipoprotein (LDL) and cholesterol crystals (Duewell et al 2010). The material internalized by phagocytes induces phagolysosomal damage and subsequent leakage of contents into cytosol to activate inflammasomes and caspase 1, and consequently the generation of interleukin-1b (IL-1β) from pro-interleukin-1β.
Interleukins are key mediators in the chronic vascular inflammatory response in cardiovascular (CV) disease and have been demonstrated in animal models and in humans to be potent modulators of pro-inflammatory processes. The fact that these cytokines and their receptors are highly expressed and are functional in almost all cell types implicated in the pathogenesis of atherosclerosis including smooth muscle cells, certain subset of macrophages and T cells as well as endothelium support the role of interleukins in vascular disease. For example, IL-1β is a potent smooth muscle cell mitogen, an activator of endothelial cells and increases extra cellular matrix and collagen deposition, which plays a role in plaque burden and arterial thickening. Furthermore, lack of IL-1β or ablation of IL-1 receptor has been shown to decrease severity of atherosclerosis in apoE deficient mice. Thus, antagonism of the IL-1β mediated inflammation is a primary and attractive target for ameliorating the vessel wall inflammation associated with atherosclerosis.
WO2010/138939 generally relates to a method of treating cardiovascular disorders with an IL-1β antibody. However it does not disclose a method of preventing or reducing risk of recurrent CV events or a cerebrovascular event.